Search Results (68)

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS) characterized by inflammation, demyelination, axonal degeneration, and gliosis. Its pathophysiology involves a complex interplay of genetic susceptibility, environmental triggers, and immune dysregulation, ultimately leading to progressive neurodegeneration and functional decline. Although significant advances have been made in disease-modifying therapies (DMTs), many patients continue to experience disease progression and unmet therapeutic needs. Drug repurposing—the identification of new indications for existing drugs—has emerged as a promising strategy in MS research, offering a cost-effective and time-efficient alternative to traditional drug development. Several compounds originally developed for other diseases, including immunomodulatory, anti-inflammatory, and neuroprotective agents, are currently under investigation for their efficacy in MS. Repurposed agents, such as selective sphingosine-1-phosphate (S1P) receptor modulators, kinase inhibitors, and metabolic regulators, have demonstrated potential in promoting neuroprotection, modulating immune responses, and supporting remyelination in both preclinical and clinical settings. Simultaneously, artificial intelligence (AI) is transforming drug discovery and precision medicine in MS. Machine learning and deep learning models are being employed to analyze high-dimensional biomedical data, predict drug–target interactions, streamline drug repurposing workflows, and enhance therapeutic candidate selection. By integrating multiomics and neuroimaging data, AI tools facilitate the identification of novel targets and support patient stratification for individualized treatment. This review highlights recent advances in drug repurposing and discovery for MS, with a particular emphasis on the emerging role of AI in accelerating therapeutic innovation and optimizing treatment strategies. Full article

Background: Amyotrophic lateral sclerosis is a systemic, complex, multifactorial, and fatal neurodegenerative disease with various factors involved in its etiology. This study aimed to understand the effects of SNPs in the MTHFR, MTR, SLC19A1, and VAPB genes on protein functionality and structure and their influence on ALS susceptibility. Methods: The dbSNP and ClinVar databases were used for SNP data annotation, while UniProt and PDB provided protein sequences. We performed functional and structural predictions of SNPs using PolyPhen-2 and SNAP2. We modeled mutant proteins using AlphaFold 2 and visualized them in PyMOL to compare native and mutant forms. Results: Our results identified SNP rs74315431 as pathogenic, inducing structural and functional changes and exhibiting visible alterations in the three-dimensional structure. Although predicted as non-pathogenic, SNPs rs1801131, rs1805087, and rs1051266 caused protein structural alterations, a finding confirmed by three-dimensional visualization. SNP rs1801133 diverged from the others, being predicted as pathogenic but without causing changes in protein structure or function. Conclusions: Our study found a strong correlation between SNAP2-predicted alterations and those predicted by AlphaFold 2, whereas PolyPhen-2 results did not directly correlate with three-dimensional structure changes. Full article

Background: Systemic sclerosis is a systemic autoimmune disease that also impacts women’s health in very different ways. Methods: This review summarises the most important data on sexuality, fertility, pregnancy, and menopause from the last 10 years. Findings: We identified nine articles with data on sexuality and a prevalence of sexual dysfunction varying between 46 and 90%. Fertility was examined in six studies, with evidence for a negative influence at least on ovarian reserve. With regard to menopause, only three studies are mentioned that show an increased risk for premature menopause in SSc women. Although pregnancies are rare in SSc women after disease onset, there is growing evidence that pregnancies are feasible but go along with a higher maternal and foetal risk compared to healthy controls. Interpretation: SSc is dominated by female gender, but aspects of women’s health influenced by the disease are still often ignored. The treating physician should be aware of the mostly negative impact on sexuality, fertility, and pregnancy and address these topics with the patients to adapt treatment and follow-up examinations to the patients’ complaints and life situation. Full article

Objectives: Systemic sclerosis-related interstitial lung disease (SSc-ILD) has high associated morbidity and mortality. With early diagnosis and treatment, we can improve clinical outcomes with immunosuppression. Some patients develop progressive pulmonary fibrosis (PPF) and are eligible for anti-fibrotic therapy. There are limited data on the incidence and prevalence of PPF in the SSc ILD cohort to guide case finding. We investigated this using data from UK tertiary Rheumatology and ILD centres. Methods: Patients with systemic sclerosis across two UK rheumatology units were identified using electronic records searched from 2021 to 2023 and were compared against established PPF diagnostic criteria. Results: 255 patients were identified. Prevalence of PPF was 5.49% and in those with established SSc-ILD, 23%. Median time to development of PPF was 5 years. In 64% of patients with PPF diagnosis, they had had systemic sclerosis for over 10 years. Incidence of PPF in patients with SSc was 3.9% and in those with known SSc-ILD 16.%. Only 50% of patients who met criteria for PPF had been referred to respiratory for consideration of antifibrotic initiation. Patients with a predominantly fibrotic baseline radiological pattern (UIP) had a trend towards development of PPF (p = 0.07). No patient with a predominantly inflammatory baseline pattern developed PPF (p = 0.021). Conclusions: Real world data have shown a prevalence of PPF in the SSc-ILD cohort of 23% with a median time of 5 years to development from diagnosis of SSc. Our data show active case finding may be incomplete and rheumatologists must be cognisant of PPF when evaluating patients with SSc. Full article

Focal and segmental glomerulosclerosis (FSGS) describes a histological pattern of injury seen by light microscopy in kidney biopsy specimens and is the end result of various injuries to the podocyte. Our understanding of this disease entity has evolved greatly since it was first described, with particular focus on changes in the classification of FSGS as a disease entity and expansion in our understanding of the underlying pathophysiology. The incidence and prevalence of FSGS and FSGS-associated end-stage kidney disease (ESKD) have increased globally, particularly in the United States; it is now the most common primary glomerular disorder in those with ESKD. APOL-1 is likely responsible for this epidemiological trend in kidney disease in the US and is an important focus of clinical trials and potential targeted therapies. Currently, the goal of treatment in FSGS is to achieve remission of proteinuria and to prevent progression to ESKD. Remission is achieved by using immunosuppressive therapies in primary FSGS, but treatment in secondary and genetic FSGS is largely supportive. Recurrent FSGS (rFSGS) post-transplantation remains a significant clinical challenge to nephrologists; current monitoring and treatment strategies are based on retrospective meta-analysis and observational studies with no clear consensus as to the optimum approach. Emerging therapies are focused on developing more targeted interventions in genetic and secondary FSGS. This review article aims to comprehensively explore this multifaceted disease entity. Full article

Introduction: Timed Twenty-Five Foot Walk (T25FW) and Patient-Determined Disease Steps (PDDSs) are measures commonly used for people with MS (PwMS). However, there is limited knowledge about the utility of using the measures to customize interventions. Aim: This exploratory study aimed to assess the correlation between T25FW and PDDS among PwMS enrolled in the Tele-Exercise and Multiple Sclerosis (TEAMS) study. Methods: The correlation was examined through a Spearman’s rho statistic for T25FW time and PDDS scores. Associations between TEAMS Intervention levels (T25FW baseline benchmarks: <6 s, 6–7.99 s, >8 s, unable to complete) and the PDDS-modified ranges (0–2, 3–4, 5–6, 7) were examined utilizing a chi-square test with Monte Carlo simulations. Results: The results showed a strong statistically significant positive correlation between the T25FW time and the PDDS scores (r_s = 0.72, p < 0.001). An additional Spearman’s correlation showed strong significant positive correlation between T25FW baseline benchmarks and PDDS-modified ranges used for intervention assignment (r_s = 0.73, p < 0.001). A chi-square with Monte Carlo simulations showed a significant association between the TEAMS Intervention Level and PDDS-modified ranges (p = 0.005). Conclusion: In conclusions, the findings suggest that T25FW, when considered with PDDSs, might offer some utility in supporting clinicians as they develop intervention strategies that consider both subjective and objective aspects. These findings also highlight the potential for integrated use of both tools in clinical decision-making, program design, and tailoring interventions to meet individual functional capabilities and self-reported disability in PwMS. Full article

Background: Falls are common among individuals with multiple sclerosis (MS), yet standard clinical mobility assessments—such as the Timed Up and Go (TUG)—may not fully capture the complexities of real-world ambulation, leading to suboptimal fall identification. There is a critical need to evaluate the ecological validity of these assessments and identify alternative tests that better reflect real-world mobility and more accurately detect falls. This study examined the ecological validity of the TUG and novel dual-task clinical assessments by comparing laboratory-based gait metrics to community ambulation in individuals with MS and evaluated their ability to identify fallers. Methods: Twenty-seven individuals with MS (age 59.11 ± 10.57) completed the TUG test and three novel dual-task mobility assessments (TUG-extended, 25-foot walk and turn, and Figure 8 walk), each performed concurrently with a phonemic verbal fluency task. After lab assessments, the participants wore accelerometers for three consecutive days. Gait speed and stride regularity data was collected during both the in-lab clinical assessments and identified walking bouts in the community. The participants were stratified as fallers or non-fallers based on self-reported fall history over the previous six months. Findings: Significant differences were observed between the TUG and real-world ambulation for both gait speed (p < 0.01) and stride regularity (p = 0.04). No significant differences were found in gait metrics between real-world ambulation and both the 25-foot walk and turn and TUG-extended. Intraclass correlation coefficient analysis demonstrated good agreement between the 25-foot walk and turn and real-world ambulation for both gait speed (ICC = 0.75) and stride regularity (ICC = 0.81). When comparing the TUG to real-world ambulation, moderate agreement was observed for gait speed (ICC = 0.56) and poor agreement for stride regularity (ICC = 0.41). The 25-foot walk and turn exhibited superior predictive ability of fall status (AUC = 0.76) compared to the TUG (AUC = 0.67). Conclusions: The 25-foot walk and turn demonstrated strong ecological validity. It also exhibited superior predictive ability of fall status compared to the TUG. These findings support the 25-foot walk and turn as a promising tool for assessing mobility and fall risk in MS, warranting further study. Full article

Introduction: Walking is perceived as the most important bodily function for persons with multiple sclerosis (pwMS) and is impaired in more than 70% of pwMS. In addition, the effect of multiple sclerosis (MS) on gait pattern increases in fast walking and during fatiguing exercises, altering the spatiotemporal gait parameters and walking reserve. Objectives: The objective of this study is to investigate the impact of a 12 min intermittent-walking protocol on spatiotemporal gait parameters and on the fatigability of pwMS, as well as the association with perceived exertion and reported symptoms of fatigue. Methods: Twenty-six persons with relapse-remitting MS and twenty-eight healthy controls (HCs) were included in this cross-sectional study. The Modified Fatigue Impact Scale and the Symbol Digit Modality Test were used to evaluate fatigue symptoms and cognitive function, respectively. Participants walked six times during an uninterrupted 2-min period. Before, during the rest periods and after the last 2 min walk, the rate of perceived exertion (RPE) was measured using the Borg Scale, and the spatiotemporal gait parameters were assessed with GaitRite. The cut-off value of 10% deceleration of the distance walked index classified pwMS into two groups: MS Fatigable (MS-F) and MS Non-Fatigable (MS-NF). One-way and two-way Analyses of variance (ANOVAs) were used to verify the effect of time and groups, respectively. Results: PwMS walked slower, travelled shorter distances, and presented shorter step lengths compared to HCs. No effects of the intermittent-walking protocol were found for all pwMS, but the MS-F group had deteriorated walking speed, step length, and cadence. Walking dysfunction was associated with perceived fatigability, reported symptoms of fatigue, cognitive function, and disability. Reported symptoms of fatigue was associated with perceived exertion but not with performance fatigability. Conclusions: Changes in gait parameters were weak to moderately associated with performance fatigability and the perception of effort and disability but not with reported fatigue symptoms, highlighting distinct constructs. The walking speed reserve and step length reserve also emerged as potential early markers of performance decline. Full article

Systemic sclerosis (SSc) is a multifaceted autoimmune disease in which the complex interplay of genetic predisposition and environmental factors triggers aberrant immune responses, ultimately leading to vasculopathy and fibrosis. This review offers a comprehensive overview of current perspectives on SSc pathogenesis, integrating classical concepts with recent breakthroughs enabled by advanced analytical techniques. We delve into the foundational trans-organ pathophysiology of SSc, encompassing epigenetic dysregulation, chronic inflammation, vascular injury, vasculopathy, and fibrosis. Furthermore, we explore the organ-specific modifiers that contribute to the heterogeneity of SSc manifestations across different organ systems, including the skin, gastrointestinal tract, lungs, and heart. Recent studies employing single-cell transcriptomics, spatial proteomics, and epigenomic profiling are highlighted, demonstrating how these technologies are revolutionizing our understanding of SSc cellular and molecular pathology. This evolving landscape of SSc pathogenesis research is critical for identifying novel therapeutic targets and advancing personalized medicine approaches for SSc patients. Full article

Background/Objectives: Late-onset multiple sclerosis (LOMS), characterized by an onset of disease at ≥50 years, is a distinct subset of multiple sclerosis (MS) with unique clinical and demographic features. While environmental factors such as smoking, diet, infections, and air pollution are well-studied in regard to early-onset MS, their roles in LOMS are not fully understood. This systematic review evaluates the environmental and clinical factors associated with LOMS risk to provide insights for prevention and management. Methods: A systematic review of MEDLINE, EMBASE, Web of Science, and Cochrane Library was conducted in accordance with PRISMA guidelines. Four studies (one case–control study, two cohort studies, and one cross-sectional study) investigating substance use, diet, disease-modifying therapies (DMTs), and demographic factors were included. Study quality was assessed using the Newcastle–Ottawa Scale (NOS), and findings were synthesized narratively. Results: Substance use, including smoking and the use of alcohol and drugs, was significantly associated with an increased LOMS risk (ORs 1.9–3.2). Diet quality showed no significant association with LOMS risk (HR = 1.02, 95% CI: 0.85–1.22). DMTs reduced disability progression (OR = 0.67, 95% CI: 0.55–0.81) and mortality (HR = 0.78, 95% CI: 0.65–0.94). Regional variations in symptoms were noted, with optic neuritis frequently reported as an initial symptom. Conclusions: This review identifies substance use as a significant modifiable risk factor for LOMS, while DMTs improve outcomes by reducing disability progression and mortality among elderly MS patients. The neutral findings for diet quality suggest a limited role in LOMS prevention. Further research is needed to explore broader environmental exposure and longitudinal outcomes to enhance understanding and management of LOMS. Full article

The mortality risk in systemic sclerosis (SSc) is primarily determined by pulmonary involvement (interstitial lung disease (ILD), pulmonary fibrosis), pulmonary arterial hypertension (PAH), and cardiac involvement. With timely and intensive treatment, the disease can be halted or even improved. Therefore, early diagnosis remains crucial. Unfortunately, biomarkers currently available cannot meet this requirement. SSc is characterized by autoimmune inflammation, vasculopathy, and fibrosis. The immunometabolic characterization of autoimmune diseases contributes to a better understanding of the underlying inflammatory processes. In this narrative review, we included 13 studies on metabolomic patterns in SSc in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA). Current studies indicate an altered metabolome in SSc. All documented significant differences between patients with SSc and healthy controls, although the observed metabolomic patterns in SSc were inconsistent between studies. Metabolome alterations include, in particular, energy-related metabolic pathways such as glycolysis/gluconeogenesis, including the synthesis and degradation of ketones, fatty acid oxidation, amino acid-related metabolic pathways, lipid metabolism, and the tricarboxylic acid (TCA) cycle, including pyruvate metabolism. The most frequently examined organ complications with reported significant aberrations of the metabolome were skin involvement, ILD, and PAH. Conclusion: The detailed characterization of the SSc-specific metabolome promises a more comprehensive understanding of the pathogenic mechanisms of the disease. Furthermore, the detection of associations between specific metabolic aberrations and disease phenotypes bears hope for new biomarkers and an improved personalized approach to diagnostics, therapy, and follow-up in the management of SSc. Full article

Background: Systemic sclerosis (SSc) is a rare connective tissue disease characterized by vasculopathy, autoimmunity, and fibrosis. Due to its low prevalence and heterogeneous clinical presentation, early diagnosis remains challenging, often delaying appropriate treatment. The disease progresses from microvascular dysfunction, manifesting as Raynaud’s phenomenon, to systemic fibrosis affecting multiple organs, including the lungs, gastrointestinal tract, heart, and kidneys. There have been considerable advancements in understanding the pathophysiology of the disease during the last few years and this has already resulted in the improvement of the therapeutic approaches used to control organ-specific manifestations. However, the underlying cause of the disease still remains incompletely elucidated. Methods: Here, we summarize the current knowledge on the SSc pathogenesis. Results: The pathophysiology involves an interplay of chronic inflammation, impaired vascular function, and excessive extracellular matrix deposition, leading to progressive organ damage. Endothelial dysfunction in SSc is driven by immune-mediated injury, oxidative stress, and the imbalance of vasoconstrictors and vasodilators, leading to capillary loss and chronic hypoxia. Autoantibodies against endothelial cells or other toxic factors induce apoptosis and impair angiogenesis, further exacerbating vascular damage. Despite increased angiogenic factor levels, capillary repair mechanisms are defective, resulting in progressive ischemic damage. Dysregulated immune responses involving Th2 cytokines, B cells, and macrophages contribute to fibroblast activation and excessive collagen deposition. Transforming growth factor-beta (TGF-β) plays a central role in fibrotic progression, while fibroblasts resist apoptosis, perpetuating tissue scarring. The extracellular matrix in SSc is abnormally stiff, reinforcing fibroblast activation and creating a self-perpetuating fibrotic cycle. Conclusions: Advances in molecular and cellular understanding have facilitated targeted therapies, yet effective disease-modifying treatments remain limited. Future research should focus on precision medicine approaches, integrating biomarkers and novel therapeutics to improve patient outcomes. Full article

Background: Amyotrophic lateral sclerosis (ALS) is a rare, incurable, and fatal neurodegenerative disease that affects the muscles and results in paralysis. The onset and development of ALS involve complex interactions among metabolic signaling, genetic pathways, and external factors (epigenetics). New biomarkers and alternative therapeutic targets have been suggested; nonetheless, the results have been unsatisfactory. Mutations in SOD1, fused in sarcoma (FUS), and TAR DNA-binding protein 43 (TDP-43) have been identified in sporadic amyotrophic lateral sclerosis and approximately 12–20% of familial amyotrophic lateral sclerosis (fALS). Aim: This review analyzes dysregulated microRNA signaling pathways and their interactions with metabolic pathways in the context of ALS progression. Significance: Despite this, biomarkers remain unreliable, and the current medications prolong life without providing a cure. Some proposed approaches to control ALS progression include balancing autophagy and apoptosis, eliminating aggregated proteins, addressing mitochondrial dysfunction, and reducing inflammation. There is a need for studies on new biomarkers, medications, and therapeutic targets. In this context, deregulated circulating microRNAs are attracting attention for new studies on ALS at various phases of the disease. Despite the extensive literature on microRNAs as potential biomarkers for ALS, the proposition for translational clinical use remains limited. Studies have indicated a significant downregulation or upregulation of microRNAs in the motor neurons of ALS patients compared with those with other neurodegenerative disorders and healthy controls. The microRNA biogenesis highlights the importance of this study. MicroRNAs regulate protein synthesis (translation); all human cells express many microRNAs. The complementary structures of microRNA sequences and their mRNA targets allow them to significantly alter cellular and physiological processes. Studies have examined these microRNAs as potential biomarkers for several physiological states and diseases. Comments: The success of these studies may lead to simple, low-cost, and efficient solutions for controlling the progression of ALS and other degenerative diseases. As a result, it is challenging to identify a specific biomarker with total reliability, as a specific microRNA that is increased in one disease phase can decrease in another. These points require careful consideration. They exhibit several complexities and varied interactions, focusing on mRNA targets. The current critical review highlights the potential of microRNAs as biomarkers for diagnosis, prognosis, and therapeutic options in ALS, and raises several points for discussion. Conclusions: The current critical review highlights the potential of microRNAs as biomarkers for diagnosis, prognosis, and therapeutic options in ALS, and raises several points for discussion. Full article

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system affecting over 2.8 million people around the world. Artificial intelligence (AI) is becoming increasingly utilised in many areas, including patient care for MS. AI is revolutionising the diagnosis and treatment of MS by enhancing the accuracy and efficiency of both processes. AI algorithms, particularly those based on machine learning, are being used to analyse medical imaging data, such as MRI scans, to detect early signs of MS, monitor disease progression and assess patient treatment response with greater precision. AI can help identify subtle changes in the brain and spinal cord that may be missed by human clinicians, leading to earlier diagnosis and more personalised treatment plans. Additionally, AI is being employed to predict disease outcomes, which could allow clinicians to tailor therapies for individual patients based on their unique disease characteristics. In drug development, AI is accelerating the identification of potential therapeutic targets and the optimisation of clinical trial designs, potentially leading to faster development of new treatments for MS. AI is also playing a critical role in MS fundamental research by promoting efficient analysis of vast amounts of single-cell data. Through these advancements, AI could improve the overall management of MS, offering more timely interventions and better patient outcomes. In this review, we discuss these topics and whether the influence of AI on diagnosis, treatment and research of MS can change the future of this field. Full article

Introduction: Cognitive impairment (CI) is recognized as a very frequent feature of persons with multiple sclerosis (pwMSs). Multiple studies have demonstrated the effectiveness of cognitive rehabilitation (CR) in improving CI linked to cerebral functional connectivity facilitation and increased strategies to cope with daily living activities. Nevertheless, there is considerable heterogeneity in the methodologies and protocols proposed to pwMSs. Aim: This study aimed to establish a current state of CR for pwMSs, among different types of healthcare providers (HCPs) in France. Methods: A Web-based survey was conducted between March and September 2024 among HCPs involved in the care of pwMSs. Results: One hundred and one HCPs involved in the care of pwMSs participated in this survey. CR was considered efficient by 97% of HCPs, especially when multimodal. Based on the responses, CR is proposed mainly following cognitive complaints, for moderate or severe cognitive disorders, and at the onset of the disease (45%). HCPs mentioned several obstacles to the implementation of CR, notably the cost of remediation (37%), and the lack of availability of both professionals (58%) and patients (51%). Conclusions: This rehabilitation requires specific tools combined with psychoeducative advice provided by multidisciplinary HCPs. Full article